Leachable & Extractable Analysis

[Orbitrap_SciLib]

The study of leachables and extractables helps to assure that products we use every day are safe and free of undesired contaminants. Studies of extractables performed on processing and production materials and on product containers and closures help to identify the potential substances that can leach into a product during production or storage over its shelf life.  Examination of a process or a product stored over time for the presence of any of these contaminants discovered during studies of extractables  determines the true leachable materials.

It is important to understand both the identity and nature of the extractable and leachable components to assure that a product will be free of potentially dangerous contamination.

Overview

Workflow Overview for Leachables & Extractables

Analysis of contact surfaces, such as the container and closure systems for extractables, is typically performed by extraction with solvent systems under aggressive conditions such as elevated temperature, long durations, or extreme pH values. The goal is to provide a sample that contains all components that could possibly leach into a stored product.  Extracted samples are analyzed by multiple techniques, in which mass spectrometry is the most prevalent.  The detection and subsequent identification of all potential leachable components is enabled by a complete understanding of the extractable components.  Mass spectrometers powered by Orbitrap™ technology make such complex analysis possible with high resolution (up to 240,000 FWHM at m/z 400) and robust mass accuracy. 

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Sample Preparation

Sample Preparation Workflow for Leachables & Extractables

Studies of extractables attempt to create a sample representing all possible compounds that may leach from a container or process element when exposed to the product. Typically, combinations of strong solvents, long time periods, elevated temperatures, and pressure changes are used to enhance the extraction. Tools like accelerated solvent extraction (ASE) can aid in sample preparation.

Minimal sample manipulation is undergone to assure the sample retains as many of the compounds extracted as possible for structure identification.

references

Best practices for extractables and leachables in orally inhaled and nasal drug products: an overvie...

Norwood DL, Paskiet D, et al.
Pharm Res. 2008 Apr;25(4):727-39.
 

Guidance on Container Closures

Food and Drug Administration
 

Final Guidance for Industry-Nasal Spray Drug Products Chemistry, Manufacturing, and Control Document...

Food and Drug Administration

Mass Spectrometry

Mass Spectrometry Workflow for Leachables & Extractables

The largely unknown nature of many leachables and extractables requires extensive de novo structure identification. Combining extremely high resolution (up to 240,000 resolution at m/z 400) with fast HCD fragmentation scanning, survey injections that provide fragmentation data on many components can be achieved.  Typically, a Top 5 approach, where the top five most-intense ions are fragmented using dynamic exclusion to assure that data on coeluting components is still acquired, provides sufficient information for fragment-based searching.  Library searches, based on mass and fragmentation, provide initial indications of the extracted components.  Reinjection to acquire MSⁿ fragmentation utilizing complementary fragmentation techniques, such as HCD and CID, provides even more structure interpretation tools.

Data Analysis

Data Analysis Workflow for Leachables & Extractables

Often the component peaks in studies on extractables can be clearly observed, and identification, rather than detection, is the critical aspect.  For studies on leachables on finished products, a differential analysis approach, comparing the stored material with original unexposed material looking for new components in the stored material is valuable, as the leached materials may be minor signals and the sample matrix is made more complex by the product being studied.  Differential analysis and library searches performed by Thermo Scientific SIEVE software are useful tools for both leachable and extractable studies to begin the process of identification. Compounds identified during extractables studies also create fragmentation-based spectral libraries that can be utilized for leachable studies later through Thermo Scientific Mass Frontier software.